Norepinephrine potentiated compositions and method of use

ABSTRACT

Novel pharmaceutical compositions containing norepinephrine releasers such as alpha-adrenergic agonists, para-sympathomimetic agonists and carbonic anhydrase inhibitors in combination with a potentiating amount of norepinephrine are disclosed. Use of such compositions, exemplified by the combination of norepinephrine and epinephrine, in an ophthalmic solution for the treatment of glaucoma is also disclosed, as well as the use of the combination of norepinephrine and a norepinephrine releaser in the treatment of congestion in the upper respiratory tract.

This is a division of appliation Ser. No. 722,177 filed Apr. 10, 1984,now U.S. Pat. No. 4,581,376 which, in turn, is a continuation ofapplication Ser. No. 488,690 filed Apr. 26, 1983 and now abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to pharmaceutical compositions containingan active agent having a modality of action whereby sympathetic neuronterminals are stimulated and l-norepinephrine is released and to methodsfor treating glaucoma, nasal congestion, chest congestion, etc. usingsuch compositions.

2. The Prior Art

Glaucoma is a term used to describe various eye disorders resulting fromexcessive intraocular pressure. Intraocular pressure is maintained atspecific levels by a combination of two factors: (1) the rate at whichaqueous humor is formed and (2) the rate at which aqueous humor leavesthe eye. If the rate at which aqueous humor is formed can be reduced,then a decrease in eye pressure should be anticipated. Likewise, if therate of aqueous humor outflow can be increased, the eye pressure shouldagain decline.

Earlier reports have indicated that drugs of many modalities of actionwere able to lower eye pressure of glaucomatous patients Such drugsinclude α-adrenergic agonists, β-adrenergic agonists, β-adrenergicblockers, p-sympathomimetic agonists and carbonic anhydrase inhibitors.Agents included in all of these groups have been reported to decreasethe rate of aqueous humor formation in the eye.

In a previously published article "The Formation and Inhibition ofAqueous Humor Production", Archives of Ophthalmology, Vol. 96, September1978, pp. 1664-1667, the present applicant and S. J. Cevario discloseddata indicating that certain sympathomimetic agents, acetazolamide (acarbonic anhydrase inhibitor) and ouabain (a cardiac glycoside) operatea vasoconstrictors to inhibit aqueous humor production through amechanism by which the drugs stimulate intraocular receptors "E-1"which, in turn, communicate with neuronal terminals where norepinephrineis released for the stimulation of adjoining α-adrenergic receptorsites. All drugs operating by such a mechanism may be considered"norepinephrine releasers". Among the sympathomimetic agents,epinephrine is perhaps most widely used in the treatment of chronicsimple (wide-angle) glaucoma. However, several problems are commonlyencountered in the treatment of glaucoma with epinephrine compositions.The drug is not always continuously effective. Prolonged use ofepinephrine in the 1-4% concentrations of commercial ophthalmicsolutions leads to pigmentation (sedimentation of the oxidized drug) andmaculopathy. Moreover, narrow-angle glaucoma is a contraindication forepinephrine because, in commercial concentrations, epinephrine producesdilation of the pupil which further narrows the angle therebyexacerbating the condition.

Various sympathomimetic drugs, have also been used in commerciallyavailable preparations for the relief of nasal and chest congestion. Inaddition to finding utility in ophthalmic solutions for the treatment ofsimple ("open-angle" or "wide-angle") glaucoma, epinephrine has beenused as the active agent (bronchodilator) in sprays for the temporaryrelief of the paroxysms of bronchial asthma. Phenylephrine has also beenused in tablets and syrups and topical sprays for the relief of nasaland chest congestion, as well as in the treatment of glaucoma. Ephedrinefinds extensive use as a bronchodilator in tablets, syrups and topicalmists. In conventional pharmaceutical preparations these compounds aremost commonly used in salt form, e.g., hydrochloride, hydrobromide,bitartrate or tannate.

One of the problems with the clinical use of the above mentioned drugsis that, within time, tachyphylaxis develops, i e., the drugs becomeineffective or remain only moderately effective. For example with regardto epinephrine, Remington's Pharmaceutical Sciences (16th Ed. 1980), p.824 states "As a topical decongestant it causes too much aftercongestionto be a first-line drug."

l-norepinephrine is a hormone which naturally occurs in the human bodyand is the essential neuro transmitter of sympathetic activity in theperipheral nervous system. l-norepinephrine, also known as levarterenol,l-noradrenaline and l-arternal, is classified as an α-adrenergic agonistand its chief physiological function is that of vasoconstriction. Thechief medical uses of l-norepinephrine are in the treatment ofhypotension and shock due to impaired vasomotor activity.

Norepinephrine has been considered to have no clinical value in thetreatment of glaucoma on the basis of findings that it has negligibleeffect in reducing ocular tension. Duke-Elder, System of Ophthalmology,Vol. XI, p. 518. Gaasterland et al in "Studies of Aqueous Humor Dynamicsin Man", Investigative Ophthalmology, Vol. 12, No. 4, April 1973, pp267-279, disclose the results of studies of the effects on aqueous humordynamics in humans using a 2% sterile solution of norepinephrine as analpha-adrenergic stimulator, a 1% sterile solution isoproterenolhydrochloride as a beta-adrenergic stimulator, a 2% sterile solution ofl-epinephrine bitartrate (an alpha and beta stimulator) and acombination of the norepinephrine and isoproterenol solutions. Thecombination provided an effect described as similar to that achievedwith epinephrine which is both an alpha and beta agonist. The studyconcluded that "the acute effect of epinephrine in young normalstubjects is comprised of two parts--reduction of aqueous flow due tobeta-adrenergic receptor stimulation and reduction of pseudofacility dueto alpha-adrenergic receptor stimulation, and that the reduction ofintraocular pressure is secondary to the addition of these two effects." A comparison of the data of Gaasterland et al for the combined use ofisoproterenol and norepinephrine with that for isoproterenol aloneindicates that the use of norepinephrine inhibited the effectiveness ofisoproterenol in lowering aqueous humor production and intraocularpressure. Administration of norepinephrine alone produced "nosignificant change" in intraocular pressure and produced an increase inaqueous flow.

SUMMARY OF THE INVENTION

It has now been discovered that a relatively small amount of locallyapplied norepinephrine serves to potentiate the pharmacologic activityof a wide range of norepinephrine releasers. This potentiating effect isparticularly evident for compositions containing low levels of thenorepinephrine releaser, e.g., 0.5 wt. % or less. The term"norepinephrine releaser", as used herein to describe the pharmacologicactivity of various active ingredients used in the compositions andmethods of the present invention, is unique and is defined by theindividual ability of hexamethonium and tolazoline to block thepharmacologic activity of that agent. See Frank J. Macri, "LocalGanglion-like Stimulating Properties of Some Adrenergic Amines whichAffect Blood Vessels of the Anterior Segment of the Eye", InvestigativeOphthalmology, Vol. 11, No. 10, pp. 838-844, Oct. 1972, the teachings ofwhich are incorporated herein by reference.

It is to be anticipated that systemic or oral administration of thecombined drugs would not be potentiative since norepinephrine is rapidlydestroyed by blood enzymes. Accordingly, the present inventioncontemplates local or topical administration only. In contrast, withlocal administration, the drugs are able to reach the α-adrenergicreceptors, which when stimulated produce a lowering of aqueous humorproduction, broncho-dilation and nasal vasoconstriction. The presentinventor has discovered that the aqueous humor action of epinephrinewhen administered to the eye is blocked by hexamethonium whereashexamethonium potentiates the blood pressure elevating action ofepinephrine administered intravenously. Accordingly, the mode of actionof the norepinephrine releaser in the eye differs from the traditionallyaccepted mode of action, i.e., its mode of action on the circulatorysystem. Further it is now believed that a norepinephrine releaser, asdescribed herein, administered topically (directly) to the nasal or lungtissue behaves pharmacologically in the same manner as when applied tothe cornea.

Studies conducted by the applicant indicate that the loss of activitycommonly seen in the administration of conventional drugs which may becharacterized as norepinephrine releasers is due to the complete orpartial loss of endogenous neuronal stores of norepinephrine. Elementarylogic dictates that if the stores of releasable norepinephrine at thenerve terminals is diminished or depleted, then the agents wich act byreleasing norepinephrine become proportionately less effective. Thepresent invention provides repletion of the norepinephrine stores in thenerve terminals and thereby (1) prevents the loss of pharmacologicactivity of the norepinephrine releaser (tachyphylaxis) and (2)potentiates the response to the norepinephrine releaser by providing ahigher concentration of localized norepinephrine released during a fixedstimulus.

Accordingly, the present invention provides a variety of pharmaceuticalcompositions containing norepinephrine and an alpha-adrenergic agonist,a para-sympathomimetic agonist, or a carbonic anhydrase inhibitor. Thepharmacologic activity of such norephinephrine releasers issignificantly potentiated simply by adding a relatively small amount ofnorepinephrine to a conventional pharmaceutical preparation containingthe norepinephrine releaser.

Various compositions of the present invention, for example, thosecontaining ephedrine and/or epinephrine in combination withnorepinephrine, also find utility as bronchodilators in the treatment ofbronchospasms associated with acute and chronic bronchial asthma,pulmonary emphysema, bronchitis and bronchiectasis. Accordingly, thepresent invention contemplates use of the combination of norepinephrineand a norepinephine releaser in a wide variety of types of medicationsincluding mists designed for topical application in the relief of nasaland bronchial congestion; nose drops; and as ophthalmic solutions forthe treatment of the symptoms of glaucoma, red eye, etc.

One particular advantage of the present invention is that it allows anorepinephrine releaser to be used in ophthalmic solutions at lowconcentrations whereby the aforementioned problems of pigmentation andmaculopathy are avoided while the potency in the relief of the symptomsof simple (open angle) glaucoma are retained at a level formerly seenonly in application of solutions containing on the order of 2 percent byweight of the drug. More importantly, the ophthalmic solutions of thepresent invention, containing relatively low concentrations ofepinephrine may also be used in the treatment of narrow angle glaucomabecause at such low concentrations, i.e., about 0.1% or lower, the pupilis not significantly dilated and the symptom is not thereby exacerbated,yet the underlying condition (excessive pressure) is effectivelytreated.

The amount of norepinephrine releaser in the compositions of the presentinvention is preferably 0.5 wt. % or less. Typically, the compositionswill contain 0.001-0.5 wt. % of the norepinephrine releaser and0.0001-0.05 wt. % norepinephrine. Typically, the ratio of thenorepinephrine to the norepinephrine releaser is about 1:10 or less.

The methods of the present invention involve the simultaneousapplication of both the norepinephrine and the norepinephrine releaser.The methods of the present invention involve the use of pharmaceuticalcompositions containing a combination of those two active agents in therelief of nasal and chest congestion, i.e., congestion in the upperrespiratory tract, and in the treatment of both wide angle and narrowangle glaucoma. Ophthalmic solutions containing the norepinephrinereleaser at a concentration of about 0.1% or less and a potentiatingamount of norepinephrine may be used for the treatment of both wide andnarrow angle glaucoma. The term "simultaneous" as used herein, hasreference to the application of norepinephrine and the norepinephrinereleaser together in a concomitant administration as well as separateadministrations of the norepinephrine and the norepinephrine releaser,e.g., within about one-hour, preferably within 5-10 minutes or less.

In another of its aspects, the present invention provides separatecompositions containing norepinephrine and a norepinephrine releaser,respectively, together in kit form.

Accordingly, it is an object of the present invention to providecompositions in which the pharmacological activity of a norepinephrinereleaser is potentiated by the inclusion of norepinephrine and methodsof utilizing such compositions.

It is a further object of the present invention to allow the use ofnorepinephrine releasers in lower concentrations while retaining thelevel of pharmacologic activity commonly provided by conventionalpreparations containing such agents, thereby minimizing undesirable sideeffects.

These and other objects and features of the present invention willbecome apparent from the detailed description of the invention tofollow.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

Norepinephrine releasers having pharmacological activity which isenhanced by co-administration with norepinephrine in accordance with thepresent invention include, for example:

α-adrenergic agonists:

epinephrine

mephentermine

methoxamine

ephedrine

hydroxyamphetamine

β-adrenergic agonists:

isoproterenol

p-sympathomimetic agonists:

pilocarpine

carbonic anhydrase inhibitors:

acetazolamide

Of the above, those groups exclusive of the β-adrenergic agonists arepreferred because of adverse side-effects on the heart produced by theβ-adrenergic agonists. Also, as previously noted, Gaasterland et alreported that the effects of isoproterenol in reducing aqueous humorflow and eye pressure, in a 1 wt. % ophthalmic solution are notpotentiated by norepinephrine and, on contrary, are reduced somewhat.However, it has now been discovered that at lower concentrations on theorder of 0.01 wt. %, the effects of isoproterenol are potentiate bynorepinephrine. Also, it is believed that at isoproterenolconcentrations of 0.1-0.01 wt. % or less the potential for adverseside-effects on the heart from use of the β-adrenergic agonist in anophthalmic solution is reduced to insignificance.

As previously noted, the compositions of the present invention includeophthalmic solutions for treament of glaucoma, red eye, etc. Theophthalmic solutions of the present invention contain norepinephrine anda nonepinephrine releaser in a sterile liquid carrier. As isconventional in pharmaceutical practice, the sterile liquid carrier willtypically be a buffered isotonic solution in either an aqueous or aviscous, e.g., methylcellulose, vehicle. Also in accordance withconventional practice, such ophthalmic solutions may contain anantiseptic preservative such as benzalkonium chloride and an antioxidantsuch as sodium bisulfite or ascorbic acid. A typical formulation forsuch an isotanic ophthalmic aqueous solution, buffered to a pH of 4.4with a sodium citrate-citric acid buffer solution and containing:

0.1 weight % epinephrine bitartrate

0.01 weight % norepinephrine

0.15 weight % sodium bisulfite

1:7500 benzalkonium chloride

Sodium chloride is typically added to adjust the osmolality, e.g., to288 mosm. (Gaasterland et al).

The combination of norepinephrine with epinephrine is consideredparticularly useful because of the body's high level of tolerance forthese substances, both of which are hormones produced naturally withinthe body. Accordingly, it is believed that side effects from use of sucha composition are negligible.

The compositions intended for use in the relief of nasal and/or chestcongestion likewise contain the norepinephrine releaser andnorepinephrine in combination with a conventional pharmaceuticalcarrier, e.g., aqueous solutions and inert propellants such ashalogenated hydrocarbons for bronchial sprays.

The examples which follow serve to illustrate the potentiating effect ofnorepinephrine on the pharmacologic activity of epinephrine inophthalmic solutions.

EXAMPLES

The following test results demonstrate the effectiveness of thecompositions of the present invention in decreasing the rate of aqueoushumor formation in the eye and indicate effectiveness in the treatmentof glaucoma. Rabbit eyes, freshly removed from their hosts, werearterially perfused and placed in individual holders. The rate ofspontaneous formation of aqueous humor was measured over a period of 0.5hour to determine the control response values reported in column (3) ofthe table below. Measurement for the controls and the drug testsemployed the procedure and apparatus described in an article co-authoredby the present applicant and J. O'Rouke entitled "Measurements ofAqueous Humor Tunover Rates Using a Gamma Probe" published in

Archives of Ophthalmology, Vol. 83 (1970), pp 741-746, the teachings ofwhich are incorporated herein by reference. In testing norepinephrinealone (Cols. 8 and 9), l-epinephrine alone (cols. 4 and 5) and thecombination thereof (Cols. 6 and 7), 50 microliters (50 μl) of each drugor drug combination was placed on the cornea, i.e., topically applied,at the end of the control period and the monitoring of the rate ofaqueous humor formation with the gamma probe was continued for anadditional 30 minutes. The values for "Response" reported under columnheadings 5, 7 and 9 are for the rate of aqueous humor formation asmeasured 30 minutes after drug administration. The results clearly showthat relatively small amounts of norepinephrine greatly enhance theeffectiveness of the epinephrine in decreasing the rate of aqueous humorformation.

The various administrations in each experiment were consecutive. Thusfor Exp. 210 the response 2.6(5) was obtained 30 minutes after the firstadministration of l-epinephine and the response 2.7(5) was obtainedafter a second application of epinephrine. In each case where a secondapplication is shown, the second application followed the first by 30minutes. Further the application of l-epinephrine and norepinephrine incombination (6) followed the administration of epinephrine by 30minutes. Thus, the results for experiments employing dual applicationsof epinephrine alone show that the potentiated composition of thepresent invention was effective to further lower aqueous humorproduction even after the maximum effect of epinephrine alone had beenrealized. The ineffectiveness of norepinephrine alone, in theconcentration used, is shown in Exp. Nos. 170-227.

    __________________________________________________________________________    Aqueous Humor Formation Rates                                                 Microliters per Minute                                                        Pre-                             l-Norepinephrine                                Treat-                                                                            Conc.                                                                             Control                                                                            Conc.                                                                             Re- Conc.                                                                              Re- Conc.                                                                             Re- % of                                 Exp.                                                                             ment                                                                              (%) Response                                                                           (%) sponse                                                                            (%)  sponse                                                                            (%) sponse                                                                            Control                              No.                                                                              (1) (2) (3)  (4) (5) (6)  (7) (8) (9) (10)                                 __________________________________________________________________________                            l-epinephrine/                                                        l-epinephrine                                                                         l-norepinephrine                                      210        6.0  .01 2.6 0.01/                                                                              2.0                                                              .01 2.7  .001                                                 168        5.3  0.1 4.5 0.01/                                                                              3.1                                                                      0.001                                                 215        5.9  .001                                                                              5.2 0.001/                                                                             2.9                                                                      0.0001                                                216        3.3  .001                                                                              2.5 0.001/                                                                             1.4                                                                      0.0001                                                218        7.4  .001                                                                              2.6 0.001/                                                                             1.5                                                              .001                                                                              3.1 0.0001                                                217                                                                              l-epi                                                                             .001                                                                              3.6  .001                                                                              3.7 0.001/                                                                             2.4                                                                      0.0001                                                219                                                                              l-epi                                                                             .001                                                                              4.3  .001                                                                              5.8 0.001/                                                                             3.0                                                              .001                                                                              5.4 0.0001                                                129                                                                              l-NE                                                                              .001                                                                              4.2          0.01/                                                                              1.4                                                                      0.001                                                 131                                                                              l-NE                                                                              .001                                                                              2.3                   .001                                                                              2.5 108                                  170        8.3                   .001                                                                              7.9 95                                   171        4.5                   .001                                                                              3.0 67                                   147        1.9                   .001                                                                              1.6 84                                                                        mean                                                                              88.5                                 223        2.2                   .0001                                                                             2.2 100                                  224        4.8                   .0001                                                                             4.3 90                                   226        5.8                   .0001                                                                             6.0 103                                  227        2.5                   .0001                                                                             2.4 96                                                                        mean                                                                              97.2                                                         l-Isoproterenol +                                                     l-Isoproterenol                                                                       l-Norepinephrine                                      166        7.3  .01 7.2  .01/                                                                              3.2                                                                       .001                                                 __________________________________________________________________________     l-epi = lepinephrine                                                          l-NE = lnorepinephrine                                                   

Although, only l-isomers have been utilized in experimentation to date,it is anticipated that the d,l-isomeric forms would be also active dueto their content of the l-isomers.

The invention may be embodied in other specific forms without departingfrom the spirit or essential characteristics thereof. The presentembodiments are therefore to be considered in all respects asillustrative and not restrictive, the scope of the invention beingindicated by the appended claims rather than by the foregoingdescription, and all changes which come within the meaning and range ofequivalency of the claims are therefore intended to be embraced therein.

What is claimed is:
 1. A pharmaceutical composition comprising: (1)0.1-0.01 wt % isoproterenol or a pharmaceutically aceptable saltthereof; and (2) 0.0001-0.05 wt % 1-norepinephrine or a pharmaceutiallyacceptable salt thereof.
 2. The composition of claim 1 wherein the ratioof isoproterenol or pharmaceutically aceptable salt thereof tonorepinephrine or pharmaceutically acceptable salt thereof is about10:1.
 3. An opthalmic solution comprising: (1) 0.1-0.01 wt %isoproterenol or a pharmaceutically acceptable salt thereof; (2)0.0001-0.05 wt % norepinephrine or a pharmaceutically acceptable saltthereof; and (3) a sterile, pharmaceutically acceptable liquid carrier.4. The composition of claim 3 wherein the ratio of isoproterenol orpharmaceutically acceptable salt thereof to norepinephrine orpharmaceutically aceptable salt thereof is about 10:1
 5. A method forthe treatment of glaucoma by simultaneously, topically administering tothe eye a solution of 0.1-0.01 wt % isoproterenol or a pharmaeuticallyacceptable salt thereof and a solution of 0.0001-0.05 wt %norepinephrine or a pharmaceutically acceptable salt thereof.
 6. Themethod of claim 5 wherein said norepinephirne or a pharmaceuticallyaceptable salt thereof and isoproterenol or a pharmaceuticallyacceptable salt thereof are co-administered in the same sterile,pharmaceutical liquid carrier.
 7. The method of claim 5 wherein saidnorepinephrine or a pharmaceutically acceptable salt thereof andisoproterenol or a pharmaceutically acceptable salt thereof areadministered in separate sterile, pharmaceutical liquid carriers.
 8. Themethod of claim 5 wherein the ratio of isoproterenol or pharmaceuticallyacceptable salt thereof to norepinephrine or pharmaceutically acceptablesalt thereof is about 10:1.1